What is the significance of the human papillomavirus in cervical dysplasia and malignancy?
Human papillomavirus (HPV) infection must be present for cervical cancer to occur.
HPV infection occurs in a high percentage of sexually active women. However, approximately 90% of HPV infections clear on their own within months to a few years and with no sequelae, although cytology reports in the 2 years following infection may show a low-grade squamous intraepithelial lesion.
On average, only 5% of HPV infections will result in the development of CIN grade 2 or 3 lesions - the recognized cervical cancer precursor
Only 40% of CIN 3 lesions progress to invasive cervical cancer with 30 years
Factors that influence the development of CIN 3 lesions:
- The type and duration of viral infection, with high-risk HPV type
- Host conditions that compromise immunity
- Environmental factors
Lack of access to routine cytology screening
Does HPV affect skin or mucosal surfaces?
HPV affects squamous epithelium
Depending on the subtype of HPV, the virus will preferentially infect either the skin or mucosal surfaces such as the cervix
What are the two most common HPV serotypes that cause cervical cancer
HPV serotypes HPV-16 and HPV-18 are the most common causes of cervical cancer
They are both high risk HPV serotypes
Characterise the natural history of HPV infection and how this leads to dysplastic changes of cervical cells
HPV infects the basal keratinocytes of cervical squamous epithelium
Upon integration into the human genome, the linearization of high-risk HPV DNA places the E6 and E7 genes in a position of enhanced replication.
E7 binds and inactivates the Rb protein - a tumor suppressor protein - which leads to uncontrolled cell proliferation
E6 binds p53 and directs its degradation - p53 then unable to detect and respond to DNA damage
The functional loss of the p53 and RB genes leads to resistance to apoptosis, causing uncensored cell growth after DNA damage and unregulated cell proliferation
This ultimately results in progression to malignancy.
Describe the genetic profile of the HPV virus
HPV has two major sets of genes:
Early Genes: E1-E7 that code for virulence factors such as replication, release, immune evasion and p53/Rb binding
Late Genes: L1-L2 that code for the virus capsid protein
HPV genome is replicated in the nucleus of host cells in the form of circular episomes
Compare the clearance rate of high risk and low risk HPV
LrHPV cleared in 4-9 months
HrHPV cleared in 12-18 months
Time course and severity of cervical dysplasia depends upon the type of HPV infection that is incurred
Where in the cervix does HPV infect?
HPV infects the transformation zone between the vaginal type squamous epithelium and uterine type glandular epithelium
It infects the basal squamous cells in this area
How are precancerous cervical squamous lesions graded?
1) HPV - initiating lesion is the HPV infection
2) Cervical Intraepithelial Neoplasia 1 (CIN 1)
3) Cervical Intraepithelial Neoplasia 2 (CIN 2)
4) Cervical Intraepithelial Neoplasia 3 (CIN 3)
- Low grade squamous intraepithelial lesion (LSIL) = HPV or CIN 1 grading
- High grade squamous intraepithelial lesion (HSIL) = CIN 2 or CIN 3 grading
The grading of cervical intraepithelial is based on identification of nuclear atypia, characterized by:
- nuclear enlargement
- hyperchromasia (dark staining)
- coarse chromatin granules
- variation in nuclear size and shape
CIN 1 = Basal 1/3 only
CIN 2 = Basal 2/3 only
CIN 3 = Full thickness dysplasia from surface to basal epithelia
What role has cytological Pap Smears had on the incidence of cervical cancer?
The reason that cytologic screening is so effective in preventing cervical cancer is that most cancers arise from precursor lesions over the course of years.
These lesions shed abnormal cells that can be detected on cytologic examination.
Using a spatula or brush, the transformation zone of the cervix is circumferentially scraped and the cells are smeared or spun down onto a slide.
The smears are screened microscopically by eye or (increasingly) with automated image analysis systems to determine if dysplasia is present and - if so - what grade it is.
What is the point of having the SIL system of classifying cervical lesions?
The squamous intraepithelial lesion classification labels lesions as either low or high grade SIL
It is a two tiered system based off the CIN system which reflects patient management options in cytology reports:
Low grade SIL = observation
High grade SIL = surgical intervention
What are condylomas?
Condylomas are benign genital warts caused by low oncogenic risk HPV infections
The surface epithelium shows characteristic viral cytopathic changes which manifest as condylocytes: nuclear enlargement and hyperchromasia
What are the two main forms of cervical cancer?
Squamous cell carcinoma is the most common histologic subtype of cervical cancer, accounting for approximately 80% of cases
Adenocarcinoma constitutes about 15% of cervical cancer cases and develops from a precursor lesion called adenocarcinoma in situ (there is no dysplastic grading of glandular adenocarcinomas)
They all develop from high risk HPV infections
What characterisistic is commonly observed in adenocarcinomas in situ?
Picket fencing of glandular epithelium with distinct outline of columnar cells
How often should females have a Pap Smear?
What is the HPV vaccine?
All women over 18 who have ever had sex are advised to have a Pap smear every two years, even if they no longer have sex
A vaccine called Gardasil has been developed that protects against the two high-risk HPV types (types 16 and 18), which cause 70% of cervical cancers in women and 90% of all HPV-related cancers in men
- It targets the late proteins of the virus that are required to infect human cells